Is CFHR5 p.Ser99fs (c.295del) pathogenic?

CFHR5 p.Ser99fs (c.295del) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). Very rare (popmax 0.00134%, afr); Associated with C3 glomerulonephritis.

What condition is associated with CFHR5 p.Ser99fs (c.295del)?

CFHR5 p.Ser99fs (c.295del) is associated with C3 glomerulonephritis (ClinVar).

How common is CFHR5 p.Ser99fs (c.295del) in the general population?

CFHR5 p.Ser99fs (c.295del) is very rare (popmax 0.00134%, afr) (gnomAD).

CFHR5 p.Ser99fs

c.295del · VCV3575788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

C3 glomerulonephritis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.72	GERP -3.5
Overall
CADD	16.35	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,874 alleles

Overall 0.000657% 1/152,130 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CFHR5
Protein: p.Ser99fs
Coding: c.295del
MANE Select: NM_030787
Type: Deletion
Location: chr1:196984002 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 99: a disulfide bond; the sushi 2 domain

Full CFHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

C3 glomerulonephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Gln250_Cys251delinsArg Uncertain significance ★★ same condition
CFHR5 p.Thr21fs Uncertain significance ★★ same condition
CFHR5 p.Gln121fs Uncertain significance ★ same condition
CFHR5 p.Lys562fs Uncertain significance ★ same condition
CFHR5 p.Thr325fs Uncertain significance ★ same condition
CFHR5 c.607+4A>G Uncertain significance ★★ same condition
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg354Gly Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfhr5-p-ser99fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown